Heart failure secondary to myocardial infarction is a major cause of morbidity and mortality in America today. Once myocardium is lost to infarction it cannot be regenerated and, therefore, the loss of contractile mass weakens the patient's heart for the rest of his or her life. For the past 20 years there has been a concerted search for interventions which would limit the amount of tissue lost with acute myocardial infarction. The most promising approach for solving this problem has been ischemic preconditioning (PC). Preconditioning the heart with a brief period of ischemia makes it resistant to infarction from a subsequent more severe ischemic insult. If this process were understood it should be possible to duplicate it pharmacologically. I propose to further investigate this phenomenon. In past funding periods of this grant I have been very successful in contributing to our understanding of the mechanism of PC. I was the first to show that adenosine receptors are-the trigger for PC. Similarly, In 1994 I proposed that protein kinase C (PKC) is an important step in this protection, a concept that is now gaining wide acceptance. Most recently I have proposed that the stress activated MAP kinase, p38 MAPK, is an important component of the signal transduction pathway distal to PKC in this system. For the next grant period I propose 4 broad specific aims. In the first aim I will attempt to identify the PKC isoform responsible for this protection using isoform- specific activators and blockers. In another aim I will measure how much mechanical benefit the heart receives when tissue is salvaged by PC using both ischemia and PC-mimetic drugs. I will test whether the presence of PC's protected state is due to translocation of a PKC isoform to a specific intracellular site. Finally, I propose to examine the role of c-jun kinase (JNK) in the PC heart.